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Pandemic influenza vaccine manufacturing process and timeline

Pandemic (H1N1) 2009 briefing note 7

6 August 2009 | GENEVA -It takes approximately five to six months for the first supplies of approved vaccine to become available once a new strain of influenza virus with pandemic potential is identified and isolated. These months are needed because the process of producing a new vaccine involves many sequential steps, and each of these steps requires a certain amount of time to complete. The vaccine development process from start (obtaining a virus sample) to end (availability of vaccine for use) is summarized below.

Activities at WHO Collaborating Centers

1. Identification of a new virus: As part of a network set up for surveillance, laboratories around the world routinely collect samples of circulating influenza viruses and submit these to WHO Collaborating Centres for Reference and Research on Influenza for analysis. The first step towards the production of a pandemic vaccine starts when a Centre detects a novel influenza virus that differs significantly from circulating strains and reports this finding to WHO.

Vaccine virus is grown in eggs because the flu virus grows well in them, and eggs are readily available.

2. Preparation of the vaccine strain (called vaccine virus): The virus must first be adapted for use in manufacturing vaccine. To make the vaccine virus less dangerous and better able to grow in hen’s eggs (the production method used by most manufacturers), the virus is mixed with a standard laboratory virus strain and the two are allowed to grow together. After a while, a hybrid is formed which contains the inner components of the laboratory strain, and the outer components of the pandemic strain. It takes roughly three weeks to prepare the hybrid virus.

3. Verification of the vaccine strain: After its preparation, the hybrid virus needs to be tested to make sure that it truly produces the outer proteins of the pandemic strain, is safe and grows in eggs. Upon completion of this process, which takes roughly another three weeks, the vaccine strain is distributed to vaccine manufacturers.

4. Preparation of reagents to test the vaccine (with reference reagents): In parallel, WHO Collaborating Centres produce standardized substances (called reagents) that are given to all vaccine manufacturers to enable them to measure how much virus they are producing, and to ensure they are all packaging the correct dose of vaccine. This requires at least three months and often represents a bottleneck for manufacturers.

Activities at vaccine manufacturers

1. Optimization of virus growth conditions: The vaccine manufacturer takes the hybrid vaccine virus that it has received from the WHO laboratories, and tests different growth conditions in eggs to find the best conditions. This process requires roughly three weeks.

2. Vaccine bulk manufacture: For most influenza vaccine production, this is performed in nine to twelve-days old fertilized hen's eggs. The vaccine virus is injected into thousands of eggs, and the eggs are then incubated for two to three days during which time the virus multiplies. The egg white, which now contains many millions of vaccine viruses, is then harvested, and the virus is separated from the egg white. The partially pure virus is killed with chemicals. The outer proteins of the virus are then purified and the result is several hundred or thousand liters of purified virus protein that is referred to as antigen, the active ingredient in the vaccine. Producing each batch, or lot, of antigen takes approximately two weeks, and a new batch can be started every few days. The size of the batch depends on how many eggs a manufacturer can obtain, inoculate and incubate. Another factor is the yield per egg. When one batch has been produced, the process is repeated as often as needed to generate the required amount of vaccine.

3. Quality control: This can only begin once the reagents for testing the vaccine are supplied by WHO laboratories, as described above. Each batch is tested and the sterility of bulk antigen is verified. This process takes two weeks.

4. Vaccine filling and release: The batch of vaccine is diluted to give the desired concentration of antigen, and put into vials or syringes, and labeled. A number of these are then tested:

for sterility

to confirm the protein concentration and

for safety by testing in animals.

This process takes two weeks.

5. Clinical studies: In certain countries, each new influenza vaccine has to be tested in a few people to show that it performs as expected. This requires at least four weeks. In some countries this may not be required as many clinical trials were done with similar annual vaccine preparation, and the assumption is that the new pandemic vaccine will behave similarly.

Activities at regulatory agencies - regulatory approval

Before the vaccine can be sold or administered to people, regulatory approval is required. Each country has its own regulatory agency and rules. If the vaccine is made with the same processes as the seasonal influenza vaccine, and in the same manufacturing plant, this can be very rapid (one to two days). Regulatory agencies in some countries may require clinical testing before approving the vaccine, which adds to the time before the vaccine is available.

The full process, in a best case scenario, can be completed in five to six months. Then the first final pandemic vaccine lot would be available for distribution and use.

Key: The arrows with dotted lines preceded by non-broken arrows indicate the time period required for the first time an activity is done (non-broken arrow line) that is then repeated (dotted arrow line). The solid lines signify that the activity takes place within a finite period.